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national institutes of health • national center for research resources
Spring 2005 critical resources for your research
MonkeyGenes FindExpression
Macaque-specific genomic toolsaid studies of
human health.
NCRRReporter
NRCover.Final.SP05 8/10/05 2:23 PM Page 1
2 NCRR Reporter : Summer 2004
FROM THE DIRECTOR INSIDESPRING 2005, VOL XXIX, NO. 2
NCRRReporter
EditorJoyce McDonald, NCRR
Managing EditorVictoria L. Contie
Publications SupervisorShirley Coney-Johnson
On the Cover: Studying gene expression in
rhesus macaques opens a window into the
genetic mechanisms underlying human health
and disease. With two NCRR-funded projects
now developing gene expression microarrays
for these monkeys, rhesus genes can finally
reveal their secrets.
PHOTO BY RICHARD T. NOWITZ/CORBIS
This quarterly publication of the National Center for Research Resourcesfosters communication, collaboration, and resource sharing in areas of current interest to scientists and the public.
Please send comments and ideas about future articles to:
Office of Science Policy and Public Liaison, NCRR/NIHOne Democracy Plaza6701 Democracy Blvd., 9th floorBethesda, MD 20892-4874Telephone: (301) 435-0888Fax: (301) 480-3558E-mail: info@ncrr.nih.govWeb site: www.ncrr.nih.gov
A Transforming Vision for Clinicaland Translational Research
As part of the NIH Roadmap for Re-engineering the Clinical Research Enter-prise, NIH recently launched an initiative that is designed to revolutionize theway that clinical and translational research is conducted at academic health cen-ters (AHCs) across the country. The goal of the initiative is to advance the aca-demic standing of clinical and translational science as a distinct discipline, and
to catalyze the development of an academic home for clinical and translational science.NCRR has been asked to implement this new and very exciting approach in coordinationwith the other NIH institutes and centers.
As many of you know from your own experiences, clinical and translational researchinvolves specialized knowledge above that required for a medical, dental, or nursing degree,or specialty certification, and is a distinct discipline with a knowledge and skill base that mustbe learned. The increasing complexity of clinical and translational research requires a pro-fessional team that may include basic scientists, skilled clinical scientists, technology experts,and highly trained nurses, coordinators, and ancillary personnel. However, setting up theseteams can be daunting for junior investigators and difficult even for more senior investiga-tors unless the institution provides a conducive environment.
Dr. Zerhouni’s vision under this initiative is to create a new home for clinical and trans-lational research science that includes degree granting programs and opportunities for cre-ative mentoring of the next generation of clinical and translational scientists. In supportinga range of academic, intellectual, and service activities, the new initiative will provide thefinancial resources and flexibility for institutions to establish an academic home that willlikely encompass the following:
You will be hearing more about this new initiative when NCRR announces funding oppor-tunities in the late summer or early fall. While NIH will make investments in this initiative,it also will require the support of the AHCs, industry, and foundations. As with all mattersrelated to biomedical research, collaboration will be essential as we work toward our ulti-mate goal of finding ways to prevent, pre-empt, detect, treat, and cure more diseases.
Barbara Alving, M.D.Acting Director, NCRR
(For more information on this initiative, see “News from NCRR,” page 15.)
C R I T I C A L R E S O U R C E S
Monkey Genes Find Expression
Macaque-specific genomic tools aid
studies of human health.
R e s o u rc e B r i e f s
7Advances in AutomatedMicroscopy
Fu n d i n g M a t t e r s
8 Bringing Veterinariansinto Biomedical ResearchProgram cultivates expertise in whole-animal
biology and microbiology.
S C I EN C E A DVA N C E S
Discovering the Heart’s Repair Cells
“Discarded” cells may be key to
mending damaged hearts.
R e s e a rc h B r i e f s
12 Virus Implicated in Lupus
12 Sleep Key to SpeechDevelopment, Songbirds Reveal
R e s e a rc h t o R e a l i t y
14 Monoclonal AntibodiesFrom laboratory tool to effective therapies.
15 News from NCRR
4
10■ Well-designed clinical studies and trials that
include enhanced protocol developmentand regulatory oversight;
■ Education, training, and career develop-ment, with an option of a clinical and trans-lational science degree-granting program;
■ Clinical research informatics and data man-agement support with attention to lever-aging efforts in healthcare informatics andfacilitating inter-institutional collabora-tions;
■ Clinical research resources, including spaceand personnel for inpatient, outpatient, andcommunity studies and patient recruitmentservices;
■ Core technologies and laboratories that pro-vide clinical research services to investigators;and
■ Pilot studies program for trainees, new inves-tigators, and new innovative projects thatneed preliminary data before garnering inde-pendent support.
NR1stHalf.Final.SP05 8/10/05 2:25 PM Page 2
NCRR Reporter : Spring 2005 3
Zebrafish Anatomy Goes OnlineA wealth of high-resolution anatomical
images of zebrafish will soon be just a
mouse-click away. NCRR has awarded
$2.7 million over five years to Keith
Cheng of the Pennsylvania State Univer-
sity College of Medicine to develop an
online atlas of zebrafish anatomy. The
freely available Zebrafish Virtual Atlas,
which already has some images posted
on its Web site, www.zfatlas.psu.edu, will
aid the many scientists who rely on
zebrafish models of human disease.
The atlas, which Cheng is developing
with Stephen Moorman of the Robert
Wood Johnson Foundation Medical
School, will eventually contain annotated
digital histology slides for every life stage
and every part of the fish—the first such
virtual atlas to be created for a
vertebrate. Visitors can use their comput-
ers as virtual microscopes, changing their
field of view and zooming in or out on
the images. The atlas also will contain
3-D reconstructions of zebrafish organs
and body structures, which will be
viewed in rotation or movies, and be
integrated with
gene expression data avail-
able at the Zebrafish Information
Network, www.zfin.org.
Computer NetworkMakes Historic LinkEarlier this year, scientists marked the
first demonstration of a powerful com-
puter link between Hawaii and the
mainland, part of a high-speed
computer network being built through
an NCRR initiative called the Lariat
Project (www.lariat-west.org). The proj-
ect is creating high-speed connections
for six Western states—Alaska, Hawaii,
Idaho, Montana, Nevada, and
Wyoming—that currently lack
sufficient access to powerful computer
networks. NCRR’s Institutional Devel-
opment Award (IDeA) Program
launched the Lariat Project in 2003
■ A researcher in California transmits micro-scopic images through the Lariat Project’scomputer link to Hawaii.
I M AG E C O U RT E S Y O F K E I T H C H E N G ( A B OV E L E F T ) C O P Y R I G H T 2 0 0 5 ; P H O T O C O U RT E S Y O F N AT I O N A L C E N T E R F O RM I C R O S C O P Y A N D I M AG I N G R E S E A R C H , U N I V E R S I T Y O F C A L I F O R N I A , S A N D I E G O ( B O T T O M )
■ The Zebrafish Virtual Atlas will showanatomical details like those in this cross-section of a zebrafish larva.
with a $10-million grant to Montana
State University-Bozeman.
In the demonstration, researchers at
an NCRR-supported advanced
microscopy resource in California trans-
mitted to colleagues in Hawaii, in real
time, images from a multiphoton laser-
scanning confocal microscope. The
images traveled over Hawaii’s first exter-
nal computer link capable of moving 10
billion bits of data per second, part of
the Lariat Project’s growing network of
high-speed connections. Lariat is the first
phase of a planned nationwide network
called IDeANet, which will serve other
states lacking adequate computer
connectivity for conducting state-of-the-
art biomedical research.
Islet Cell Program NowServes Basic ScienceNCRR’s Islet Cell Resource (ICR) Program
is now making human islet cells available
to researchers engaged in basic scientific
research. Until now, the program, which
funds 10 ICR Centers nationwide, had
provided islet cells only to clinical
researchers, who then transplanted them
into patients with severe type 1 diabetes.
Basic researchers whose projects are
approved by the ICR Program’s steering
committee can receive islet cells at no
cost. The application form to obtain the
islets can be accessed at the ICR Web site
at http://icr.coh.org/info_invest.asp. Appli-
cants must describe why the islets are
needed and how they will be used, out-
lining the specific research objectives, the
methods to be employed, and the ratio-
nale for the number of islets requested.
Once approved, applicants can arrange
to receive islets from a specific ICR. ■
QUICK TAKES New tools and updates from NCRR resources
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4 NCRR Reporter : Spring 2005
CRITICAL RESOURCESTO O L S A N D T E C H N O LO G I E S TO E N H A N C E YO U R R E S E A R C H
Macaque monkey geneshave a lot to say, and researchers
are finally getting a chance to
listen. Genomic tools now being
developed by NCRR-support-
ed scientists will provide the
research community with
unprecedented opportunities to find out when and where
genes are being turned on, or expressed, in rhesus monkeys,
the macaque species most commonly used in biomedical
research.
Although studies of macaques play a key role in our under-
standing of human reproduction, development, and disease,
crucial genomic tools called microarrays have been lacking for
these animals. A microarray is a small, flat plate spotted with
thousands of molecular probes. Binding between these probes
and fluorescently labeled DNA or RNA samples from various
tissues reveals patterns of gene expression in the sampled tis-
sues, shedding light on a variety of biological processes. Two
NCCR-funded projects are now developing microarrays to
study the expression of rhesus genes.
“Being able to use microarrays to do sophisticated
genomics analyses is going to revolutionize the utilization
of the macaque animal model,” predicts Michael Katze,
director of the Primate Genomics Division of the NCRR-
supported Washington National Primate Research Center at
the University of Washington. Katze, a professor of micro-
biology at the university, is spearheading one of the two
rhesus microarray projects.
Monkey Genes Find ExpressionMacaque-specific genomic tools aid studies of human health.
BY SCOTT J. BROWN
LOOKING AT THOUSANDS
OF GENES AT A TIME
Microarrays allow scientists to determine
how various portions of the genetic blue-
print harbored in cells become activat-
ed,or expressed,as the body develops,car-
ries out its normal functions, and
responds to disease.An expressed gene is
one that has been switched on by having
its DNA sequence transcribed into mes-
senger RNA (mRNA),allowing the gene’s
protein product to be produced within the cell. Unlike other tech-
niques for studying gene expression,microarrays allow researchers
to study the expression of thousands of genes simultaneously.
To produce microarrays,scientists collect—from various tissues—
mRNA transcripts for expressed genes. They then create and clone
DNA molecules that have sequences complementary to the mRNAs,
called complementary DNAs, or cDNAs. These cDNA clones are
then sequenced, and portions of those sequences are used to cre-
ate short segments of synthetic,single-stranded DNA or RNA called
oligonucleotides,which serve as the microarray probes.Labeled DNA
or RNA samples derived from tissues will bind to probes that have
sequences complementary to their own. If a sample binds to a
probe, that binding reveals that the gene represented by the probe
is expressed in the tissue that generated the sample.
Up to now, macaque researchers have been forced to examine
the expression of one macaque gene at a time or have used human
microarrays to study macaque gene expression. Although the
human-microarray approach allows many genes to be studied at
■ Microarrays beingdeveloped for rhe-sus macaques prom-ise to revolutionizestudies of humanreproduction, devel-opment, and dis-ease that depend onthese animals.
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NCRR Reporter : Spring 2005 5
once, some genes expressed in macaques will not be detected by
human microarrays because of slight genetic differences between
macaques and humans.
FROM GENOMICS TO PROTEOMICS
To provide researchers with macaque-specific genomic tools,Katze
is working with Illumigen Biosciences, Inc., a biotechnology
company in Seattle, to create libraries of cDNA clones from var-
ious macaque tissues. These clones are being sequenced to gen-
erate oligonucleotide probes and to create, in collaboration with
Agilent Technologies, two gene-expression microarrays for the
rhesus macaque. One of the microarrays, completed last sum-
mer, will soon be available for purchase from Agilent. The
microarrays consist of glass plates the size of microscope slides
containing thousands of rhesus sequences as well as some human
sequences for comparative purposes.
The first microarray contains nearly 8,000 unique rhesus
oligonucleotide sequences derived from cDNAs from a wide range
of rhesus tissues.A second-generation microarray, slated for com-
pletion this summer, is expected to harbor more than 20,000 rhe-
sus oligonucleotides. It will be based not only on Illumigen’s ongo-
ing cDNA sequencing, but also on sequences provided by the
other NCRR-funded rhesus microarray initiative and by an ongo-
ing rhesus genome project at Baylor College of Medicine. The
sequences contained on the microarrays are being deposited in
NIH’s freely accessible GenBank database.
Many expression microarrays use oligonucleotide probes
that contain sequences only from the noncoding regulatory end
of a gene. Katze’s probes, however, include the protein-coding
regions of expressed genes, allowing scientists to see how gene
expression correlates with protein production. Katze is among
the many macaque researchers who will benefit from this type
of microarray. His NCRR-funded investigations examine viral
infection in macaques, including simian immunodeficiency
virus (SIV) infection, a model for HIV infection and AIDS. Such
studies depend on understanding how viruses alter the animals’
gene expression and protein production.
“By using the microarrays at both the RNA and protein level,
we can identify molecular signatures of virulence or pathogen-
esis, which could be used both diagnostically and prognostical-
ly,” says Katze. The microarray analyses also shed light on host
responses, help to reveal how viruses operate, and uncover the
genes and cellular pathways that viruses impact. “That knowl-
edge will allow us to become more adept at developing antivi-
ral therapeutics and vaccines,” he says.
MONKEY GENOME ON A CHIP
The other NCRR-funded microarray project is producing a
more comprehensive microarray designed to represent all of
the genes expressed in the rhesus macaque. Robert Norgren, asso-
ciate professor of genetics, cell biology, and anatomy at the Uni-
versity of Nebraska Medical Center, and Eliot Spindel, senior sci-
entist at the NCRR-supported Oregon National Primate Research
Center at Oregon Health and Science University, are nearing com-
pletion of a microarray that will contain some 20,000 rhesus
sequences.Affymetrix will manufacture the new rhesus microar-
ray, which should be available for purchase by this summer.
With technology borrowed from the computer industry,
Affymetrix uses quartz chips to create thumbnail-sized microar-
rays called GeneChips.
“The rhesus GeneChip is going to have a huge impact.A num-
ber of prominent investigators have told me that it will greatly
accelerate the speed of their research,”says Norgren, who empha-
sizes the advantages of microarrays over single-gene approach-
es. “To try to guess which rhesus genes are important and then
to study one gene at a time is just a painfully slow, incredibly
inefficient, and frustrating way to do things,” he says, “especial-
ly when you know this microarray technology now exists that
allows you to look at all the genes at once and be done with it.”
Scientists who have expressed interest in the rhesus GeneChip
P H O T O B Y R A N DA L L C . K Y E S , U N I V E R S I T Y O F WA S H I N G T O N
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6 NCRR Reporter : Spring 2005
are studying differentiation of rhesus embryonic stem cells,devel-
oping rhesus models of human reproductive biology, using SIV-
infected macaques as a model for AIDS, and, like Norgren, inves-
tigating rhesus models of human neurological diseases.
“The biggest group of users will undoubtedly be the people
who study AIDS,”says Norgren.“Those people are desperate for
a rhesus macaque GeneChip. I can imagine their frustration in
not having the same tool for their animal model that they have
for their human patients. They’re storing their samples, getting
ready to buy this GeneChip as soon as it’s available.”
MAKING USE OF THE HUMAN GENOME
Norgren came up with a novel way to produce the rhesus
sequences necessary for the chip. His method relies on the close
genetic similarity between
humans and macaques and
makes use of a preexisting
Affymetrix GeneChip for the
entire human genome.“The idea
occurred to me that you could
produce these sequences rela-
tively fast and relatively cheap-
ly by taking advantage of the
human genomic resources
already available,” he says.
Affymetrix created each of the
probes on its human GeneChip
from a selected region at the reg-
ulatory end of each gene, called
the probe selection region (PSR).
Norgren’s team designs oligonu-
cleotide primers whose sequences match sequences flanking the
human PSRs. The researchers then use the human primers in a
polymerase chain reaction (PCR) to amplify sequences in rhesus
genomic DNA that match the human PSRs. The PCR amplifies
rhesus sequences that are homologous to the human PSRs. These
sequences, therefore, come from rhesus genes that are homolo-
gous to human genes. This strategy is thought to capture almost
all rhesus genes, since the vast majority of rhesus genes have coun-
terparts in the human genome.
The PCR products containing the rhesus sequences are
cloned and sent to Eliot Spindel in Oregon. Spindel sequences
the clones and annotates each of the sequences. He then places
the annotated sequences, plus the primer sequences and PCR
conditions used to generate them, in the GenBank database.
“By making public the sequence information and how we got
it, other people can use that information to make their own
microarrays if they wish,”notes Norgren.Affymetrix is using these
rhesus sequences, plus sequences from the rhesus genome proj-
ect and Katze’s microarray project, to create the thousands of
oligonucleotide probes that will make up the rhesus GeneChip.
After the GeneChip is out, Norgren says he will work to close
any gaps in gene coverage that may exist on the microarray. He
also foresees additional applications for the primers used to
generate the rhesus gene sequences. These primers might help
to generate sequences from other nonhuman primates, he says,
noting that researchers who use African green monkeys have con-
tacted him and expressed interest in a GeneChip for that species.
Norgren also would like to use the primers to discover muta-
tions in rhesus genetic sequences known as single-nucleotide
polymorphisms, or SNPs, which
consist of substitutions of one
base molecule for another in the
DNA sequence. He notes that
researchers could use rhesus SNPs
to determine the genetic profiles,
or genotypes,of individual mon-
keys,allowing them to choose the
best animals for particular dis-
ease models. Rhesus SNPs also
could serve as genetic markers to
identify possible disease genes.
Norgren and Katze both
view NCRR’s support as vital
to making rhesus expression
microarrays a reality.“The sup-
port from NCRR has been
absolutely fantastic,” says Norgren. “Thanks to NCRR, many
people funded by other NIH institutes will be able to do great
things with these tools. It’s going to pay off in a big way.” ■
TO GAIN ACCESS: The Web site for the Affymetrix GeneChip Consortia Pro-
gram (www.affymetrix.com/community/research/consortia.affx) will provide infor-
mation on the availability of the rhesus GeneChip and how to order it. The consor-
tia program designs and produces GeneChips for species identified as high-priority
by the research community. Affymetrix’s NetAffx Web site (www.affymetrix.com/
analysis/index.affx) will provide the specific sequences contained in the rhesus
GeneChip probes. Robert Norgren’s Macaque GeneChip Web site (http://
rhesusgenechip.unomaha.edu) includes information on some of the genes covered
by the GeneChip, plus links to GenBank records for sequences from those genes.
The rhesus microarrays being produced by Michael Katze and Illumigen should be
available this summer from Agilent Technologies (www.agilent.com). In the mean-
time, Illumigen has an NCRR-funded Web site (www.macaque.org) with links to
GenBank records for sequences used in creating the microarrays. The site also gives
details on Illumigen’s cloning and sequencing efforts and provides information on
ordering macaque cDNA clones.
P H O T O B Y M A R C S TAC Y
■ Michael Katze’s microarrays cover the coding regions of macaquegenes, helping researchers to understand how gene expression cor-relates with protein production.
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NCRR Reporter : Spring 2005 7P H O T O B Y H E W I T T / G A R R I S O N A R C H I T E C T U R A L P H O T O G R A P H Y, S A N D I E G O
RESOURCE BRIEFS
Advances in Auto-mated Microscopy
Biomedical researchers have a new ally in
their quest to understand the inner workings of
cells. An NCRR-supported resource is automating
the laborious process of cryo-electron microscopy
(cryo-EM), currently the best technique for visual-
izing so-called molecular machines—the large macromolecular
complexes of proteins that carry out most cellular activities.
The National Resource for Automated Molecular Microscopy
(NRAMM) at The Scripps Research Institute (TSRI) in La Jolla,
California, is striving to automate the entire cryo-EM process,
from inserting the specimen into the microscope to creating a
3-D reconstruction of a molecular machine. The resource,
launched in 2003 with NCRR support, hopes to free cryo-EM
from dependence on long hours of microscopist labor, making
the technique more attractive to researchers.
“By automating, we’re hoping not only to enable different
kinds of analyses to be done, but also to open up this technique
more to the mainstream biologist,” says Bridget Carragher, who
codirects NRAMM with Clint Potter, both associate professors in
TSRI’s department of cell biology.NRAMM’s advances in automa-
tion include a robotic system to load negatively stained specimens
into the electron microscope for rapid screening, as well as auto-
mated tools to acquire and process cryo-EM images.
Because cryo-EM specimens are prepared by rapid freezing,
complex structures like molecular machines are preserved intact.
Many individual macromolecules, referred to as particles, are
trapped in a layer of glass-like ice spread over a film of carbon
mounted on a metal grid.
NRAMM has developed a software system called Leginon
to acquire images of particles frozen on a grid. The Leginon sys-
tem scans the grid, zeroes in on areas that contain the best par-
ticles, and then creates high-magnification images of particles
in those areas and captures the images on micrographs. In a typ-
ical 24-hour session, the Leginon system acquires about 500 to
1,000 pairs of high-magnification images, which together con-
tain anywhere from 10,000 to 300,000 particles, depending on
the particle size and distribution.
As a result of Leginon training courses provided by NRAMM,
12 outside groups now have Leginon available at their own lab-
oratories. Leginon has a Web site (http://leginon.scripps.edu)
from which academic and nonprofit institutions can freely
download the software.
Cryo-EM images acquired by the Leginon system are then ana-
lyzed by NRAMM-developed software,which automatically selects
thousands of individual particles that best represent the structure
of a macromolecule. Data from those particles are then averaged
to create a composite 3-D reconstruction of the macromolecule,
called a 3-D map. For this procedure, NRAMM uses reconstruc-
tion software developed by other NCRR-supported microscopy
resources, (see NCRR Reporter, Summer 2004, pages 4-7).
Carragher, Potter, and colleagues now are working to link
Leginon to the 3-D reconstruction software, thereby incorpo-
rating the construction of 3-D maps into the automated cryo-
EM process. Linking Leginon to the reconstruction software
should reduce the time needed to go from particle images to a
3-D map and further reduce the operator’s burden in supervis-
ing the overall process.
NRAMM also has created a database to keep track of all images
acquired with the Leginon system, as well as settings and parame-
ters associated with those images. The database currently contains
records on about 500,000 images from more than 50 projects.
Researchers can view the images and query database records using
Web-based tools that come with Leginon and can also view and
download certain database images from the NRAMM Web site.
All of the automated tools housed at NRAMM are available
to researchers for their cryo-EM projects. Outside researchers
also can collaborate with NRAMM scientists on projects to
enhance the resource’s automated technologies. “People don’t
necessarily have to spend two to three years training a post-
doctoral researcher to do cryo-EM,”says Potter.“They can come
to our resource instead.” —SCOTT J. BROWN
TO GAIN ACCESS: Researchers can apply to use the National Resource for Auto-
mated Molecular Microscopy (NRAMM) by filling out an online application on the
resource’s Web site (http://nramm.scripps.edu). NRAMM’s Web site also provides
access to the resource’s cryo-EM database and software and gives information about
NRAMM’s automated cryo-EM technologies and training courses. For further
information about NCRR-supported resources in biomedical technology, visit
www.ncrr.nih.gov/biomedical_tech.asp.
■ Researchers set up and monitor their cryo-electron microscopyexperiments from this state-of-the-art control room at NRAMM. Thelarge screens display images acquired by the microscope as well asresults of image analysis and processing.
NR1stHalf.Final.SP05 8/10/05 2:25 PM Page 7
FUNDING MAT TERS
Bringing Veterinarians intoBiomedical Research
Program cultivates expertise in whole-animal biology and microbiology.
As comparative medicine makes
increasingly important contributions to
biomedical science, the research community
has a growing need for investigators with
expertise that spans from molecular biolo-
gy to the epidemiology of diseases in laboratory animal mod-
els. Yet biomedical researchers who are proficient in both vet-
erinary science and biology are something of a rarity in the
scientific community.
To encourage veterinarians to consider a career in bio-
medical research, NCRR offers Institutional Research Train-
ing Grants, called T32s.
Awards are made direct-
ly to universities and
other research institu-
tions that are in a posi-
tion to provide advanced
training in comparative
medicine or compara-
tive pathology. T32
grants allow institutions
to offer integrated cours-
es of study drawn from
a variety of academic
disciplines.Trainees typ-
ically supplement their
earlier clinical or pathol-
ogy-related experience
with formal instruction
in ethics and experi-
mental design, as well as
basic science disciplines,
such as biochemistry or
molecular biology. And
most important, they
gain research experience
in areas spanning the
biomedical sciences.
The current shortage of veterinarians who know their
way around a molecular biology laboratory is one reason for
NCRR’s vigorous support of the T32 program, says Franziska
Grieder, associate director of comparative medicine at NCRR.
“In biomedical research, it’s essential to have well-trained
veterinarians who understand not just a cell but the whole
organism,” she says.
Universities have flexibility in how they organize their
T32 programs. The University of Washington School of Med-
icine, for example, requires participants to work toward a grad-
uate degree, though not all T32 programs do so. First-year
participants in the
Washington program
receive training in lab-
oratory animal medi-
cine and pathology and
participate in animal-
based research first-
hand. Trainees also
learn about research
methods and ethics
through courses and
laboratory rotations,
including a stint at the
NCRR-supported
Washington National
Primate Research Cen-
ter. In their second year,
trainees begin to pur-
sue advanced degrees in
comparative medicine
■ Rachel Mo Peters is pur-suing her Ph.D. in compara-tive biomedical sciences atCornell University with sup-port from an NCRRInstitutional ResearchTraining Grant. The grantsprovide essential training toprepare veterinarians forcareers in biomedicalresearch.
8 NCRR Reporter : Spring 2005 P H O T O B Y A L E X I S W E N S K I - R O B E RT S
NR1stHalf.Final.SP05 8/10/05 2:25 PM Page 8
or pathology or a basic science of inter-
est to them.
“Our mission is broad: to take vet-
erinarians and offer them the opportu-
nity to get research training,”says Denny
Liggitt, who directs the university’s T32
program. The program stresses what
Liggitt describes as “hardcore research,”
preparing veterinarians to become
collaborators with other medical
researchers. Many graduates go on to
work at academic institutions, includ-
ing medical schools, while others enter
private industry.
“The T32 program is extremely
important for getting veterinarians into the medical research
arena,” Liggitt says. “Graduates of the program provide a per-
spective on research that a lot of veterinarians don’t have.”
The University of Washington program typically has six
T32-funded participants at any given time and has no trou-
ble attracting candidates, Liggitt says. “We create a posi-
tive environment for young people interested in research,
and they prosper. We really have been fortunate to have this
program,” he says.
One beneficiary of the Washington T32 program is vet-
erinarian F. Claire Hankenson, who is today an assistant pro-
fessor at the University of Michigan Medical School, where
she teaches veterinarians, also funded by a T32 grant, and advis-
es scientists who use animal models in their research. After
graduating from Purdue University’s School of Veterinary
Medicine, Hankenson spent four years in the University of
Washington’s T32 program, earning a master’s degree in
microbiology in 2001. “I had an excellent experience there.
It was a very stimulating environment,” she says. The pro-
gram enabled her to merge her interests in clinical work and
basic research. Graduates of the program find that their
unique combination of skills makes them attractive to poten-
tial employers, Hankenson says.
At Cornell University’s College of Veterinary Medicine,
the T32 program offers participants the opportunity to
study biochemistry, cell and molecular biology, biomedical
ethics, laboratory technology, and biostatistics, all under
close faculty supervision. Trainees also participate in a sem-
inar series on comparative medicine,
designed specifically for program par-
ticipants, says Douglas McGregor,
director of training initiatives at the
veterinary school.
Cornell requires participants to
enroll in a doctoral program, and grad-
uates finish with highly marketable skills,
including a solid understanding of how
to prepare a research proposal, McGre-
gor says.“Industry is desperate for these
people,” he says. McGregor, an M.D.,
believes T32 graduates bring a much-
needed, broad perspective to their
research pursuits, a perspective that is
sometimes lacking in classically trained medical researchers.
Some participants in the Cornell program have earned
degrees in epidemiology, making them uniquely qualified to
tackle research issues related to infectious diseases, from bird
flu to bioterrorist attacks. “These trainees will be critical to
the nation’s biodefense structure,” says McGregor.
In recent years, the number of students in NCRR’s T32
program has doubled, with about 80 trainees now partici-
pating.“The program is geared toward research,”says NCRR’s
Franziska Grieder, “but the broad education that trainees
receive also will help equip them to take on leadership posi-
tions within the biomedical research community.”
–PHILIP BULMAN
APPLY FOR FUNDING: NCRR supports research training and career
development in comparative medicine through Institutional Training
Awards, including three types of T awards. The two universities featured in
this article received T32 awards as part of the Postdoctoral Program for Vet-
erinarians. All applicants to the postdoctoral program must have completed
their veterinary medical training. The other T32 options, which also go
directly to the university or research institute, focus on predoctoral students.
These programs—the Predoctoral Program for Veterinary Students and the
Summer Program for Predoctoral Veterinary Students—allow veterinary
students interested in biomedical research to participate in a one-year or
summer program that provides a mentored, animal-oriented research expe-
rience. Trainees must have undergraduate degrees, be enrolled in a veteri-
nary degree program, and be willing to devote 40 hours a week to the pro-
gram. The third program is funded under the T35 mechanism and provides,
directly to the university or institution, funds for short-term summer
research training for veterinary students.
For more detailed information about NCRR’s T32 awards, visit
www.ncrr.nih.gov/compmed/cm_rcdtf.asp.
■ F. Claire Hankenson benefited from the T32program as a graduate student. Today she teachesveterinarians who participate in the T32 programat the University of Michigan.
NCRR Reporter : Spring 2005 9P H O T O B Y K D H
[ ]“The T32 program is extremely important for getting veterinarians into the medical research arena.”
NR1stHalf.Final.SP05 8/10/05 2:25 PM Page 9
10 NCRR Reporter : Spring 2005
SCIENCE ADVANCESD I S C O V E R I E S E N A B L E D B Y N C R R R E S O U R C E S
Discovering theHeart’s Repair Cells “Discarded” cells may be key to mending damaged hearts.BY TINA ADLER
Tucked deep in the newborn’s heart are
malleable progenitor cells capable of grow-
ing into mature heart cells, researchers
recently discovered. The finding represents
the first strong evidence that progenitor cells
survive, at least for a few days, after birth.
The tissue containing these valuable
cells is normally discarded when newborns undergo cardiac
surgery. But researchers now hope that someday the cells
may be harvested to help restore tissue in heart attack patients
or to function as biological pacemakers.
Molecular cardiologist Kenneth
Chien and his colleagues first found
the progenitor cells, called isl1+ car-
dioblasts, in developing mouse and rat
embryos. The researchers then iden-
tified the cells in five out of six human
infants undergoing heart surgery.The
cells’ identities were verified by using
the high-speed, multiphoton, laser-
scanning microscope at the NCRR-
funded National Center for
Microscopy and Imaging Research,
directed by Mark Ellisman at the Uni-
versity of California, San Diego.
“Ellisman’s technology was par-
ticularly important to distinguish
progenitors from mature cells—to
identify the cells and compare their
properties,” says Chien, director of the Cardiovascular Research
Center at Massachusetts General Hospital. With the high-reso-
lution microscope at the NCRR-supported resource, says Chien,
“we were able to monitor, in real time, the flux of calcium
between progenitor cells and the cardiac muscle cells to show
they were working compatibly.”
Three studies since 2003 by other research groups have identi-
fied stem cells in the adult human heart,but these unspecialized cells
can divide to produce any type of cell. Progenitor cells, in contrast,
give rise to a distinct cell lineage, says Chien.“Our story is unique,
because the cells we found can become—and spontaneously do
become—fully functional cardiac mus-
cle cells,”says Chien.Other researchers
had identified single cells that had mus-
cle-cell characteristics but did not
become functioning muscle cells.
Chien’s team found not just one
cell but a few hundred of the pro-
genitor cells in the hearts of new-
born humans, mice, and rats. In all
of these species, the progenitor cells
were in the heart’s myocardium,
which is the middle and thickest layer
of cardiac muscle in the heart wall.
By placing the cells on a layer of con-
nective-tissue cells, called fibroblasts,
Chien’s group was able to produce
millions of offspring of the progen-
itor cells. About 30 percent of the
I M AG E B Y K A R L - LU D W I G L AU G W I T Z , U N I V E R S I T Y O F C A L I F O R N I A , S A N D I E G O
■ Researchers were surprised to discover progenitor cells(green) in the cardiac muscle (red) of a newborn mouse, asthose cells were not thought to survive after birth. Cellularnuclei are shown in blue.
NR2ndHalf.Final.SP05 8/10/05 2:26 PM Page 10
NCRR Reporter : Spring 2005 11
offspring cells differentiated into complete cardiac muscle cells.
Chien and his colleagues came upon the progenitor cells by tak-
ing a closer look at material that they once considered disposable.
During their many years of studying heart tissue, the researchers
typically separated out and discarded the nonmuscle cells from their
samples.But when they finally examined some nonmuscle cells that
had been left in a culture medium for two weeks, the cells appeared
to be differentiating into cardiac muscle.The activity was occurring
in tiny islands where there were cardiac fibroblasts, which the team
now knows serve as a growth medium for the progenitor cells.
After seeing the cells in action, the team needed a way to iden-
tify them. Fortunately, Chien’s colleagues in a nearby laboratory
had recently identified a marker, called islet-1, that distinguished
progenitor cells in the embryonic heart.By searching for the mark-
er, Chien’s group discovered that the progenitors in the newborn
rats, mice, and humans were all expressing islet-1.
In hypothesizing why the cells remain in the heart after birth,
Chien says that the progenitor cells may be important in remod-
eling the newborn’s heart. Congenital heart defects may arise if
the lingering cells are defective. Other researchers have experi-
mented with injecting adult stem cells into patients’ hearts to
repair damage from heart attacks (see sidebar), but the results
of these efforts have been mixed. Chien asserts that successful
use of progenitor cells to heal heart attack patients is years away.
Whether progenitor or stem cells prove better at restoring
healthy muscle in heart attack patients will depend on many fac-
tors, including which type of cell can best be grown in large num-
bers. The cells must take on the complex role of making elec-
trical connections with other cells. Without those connections,
Chien says, fatal arrhythmias may result. ■
The research described in this article depended on technologies developed at the
NCRR-supported National Center for Microscopy and Imaging Research at the Uni-
versity of California, San Diego. For information about other NCRR-funded bio-
medical technology resources, visit www.ncrr.nih.gov/biomedical_tech.asp.
ADDITIONAL READING■ Laugwitz, K. L., Moretti, A., Lam, J., et al., Postnatal isl1+ cardioblasts enter fully
differentiated cardiomyocyte lineages. Nature 433:647-653, 2005.
Patients who survive a heart attack are
not necessarily in the clear. The episode
creates scar tissue, which increases a
patient’s risk of developing complications.
To help heal damaged hearts, researchers
are experimenting with injecting the build-
ing blocks of heart muscle into the patient’s
damaged organ.
One such study has recently begun at
the Johns Hopkins University School of
Medicine, with assistance from the NCRR-
supported General Clinical Research Cen-
ter (GCRC). Researchers are injecting
adult mesenchymal stem cells, which
come from the bone marrow of adult
donors, into recent heart attack victims
to test the safety of the treatment. The Bal-
timore-based company Osiris Thera-
peutics developed the stem cell product
and is supporting the study.
As of April 2005, the team had treated
its first patient and had plans to treat an addi-
tional 47 patients,says cardiologist and sen-
ior investigator Joshua Hare, professor of
medicine at the university. The GCRC is
invaluable to this kind of research, he says.
“We couldn’t do the study without the
GCRC, because it’s a four-day in-patient
study, and patients must be very carefully
monitored.” Staff from the Johns Hopkins
stem cell laboratory are working with GCRC
nurses to administer the infusions.“It’s a big
team effort,” Hare notes.
In one recent study, reported in
November 2004 at the American Heart
Association Scientific Sessions confer-
ence in New Orleans, the team adminis-
tered the stem cells to pigs with dam-
aged hearts. Up to 75 percent of the dead
scar tissue in the animals’ hearts disap-
peared after the treatment. “When we
looked at the function and structure of
the animals’ hearts, we found growth of
new, normal cardiac tissue and really dra-
matic cardiac repair,” says Hare.
In the human trial, candidates first
undergo catheterization and echocardio-
graphy to ensure their main coronary ves-
sels are not blocked. The participants then
receive one of three possible doses of stem
cells or a placebo. The stem cells, which do
not trigger the body’s immune system, are
expected to migrate to the damaged areas
of the heart muscle.
How mesenchymal stem cells may work
to repair heart tissue is unclear. Mes-
enchymal cells normally give rise to a vari-
ety of cell types, including bone, cartilage,
fat, and other kinds of connective-tissue
cells.“There’s some evidence that the cells
differentiate into cardiac muscle cells and
some evidence that they do not, but the
larger area of controversy is whether dif-
ferentiation is necessary for cardiac repair,”
says Hare. In the pig study, for example, the
team saw no evidence that the cells had
differentiated. Hare suspects that the mes-
enchymal cells do not become muscle cells
but rather release growth factors and other
molecular signals that elicit repair.
Hare is eager to bring the efforts of
basic research to the clinic. “The ultimate
goal of our research is the rapid translation
of basic science into treatment,” he says.
ADDITIONAL READING■ Bhatia, R., Hare, J. M., Mesenchymal stem cells:Future source for reparative medicine. CongestiveHeart Failure 11:87-91, 2005.
Sending in the Repair Cells
NR2ndHalf.Final.SP05 8/10/05 2:26 PM Page 11
These findings may lead to better diagnosis and treatment
of lupus and may also aid a project at the OMRF, also support-
ed by COBRE funding, to develop an EBV vaccine, says James.
She and her colleagues next plan to explore genetic factors that
might explain why most people infected with EBV produce anti-
bodies to Ro only transiently or not at all, while individuals who
go on to develop lupus make the antibodies for prolonged peri-
ods and progress to a more complex response. The researchers
also want to enroll and follow patients through the University
of Oklahoma’s GCRC to determine how EBV-induced autoim-
mune responses to Ro might lead to clinical lupus symptoms.
(Nature Medicine 11:85-89, 2005) —SCOTT J. BROWN
NCRR RESOURCES: The Center of Biomedical Research Excellence (COBRE) at
the Oklahoma Medical Research Foundation is among more than 70 COBREs across
the country (see NCRR Reporter, Winter 2004, pages 5-7). The COBRE Program
funds researchers in states that historically have received fewer competitive research
grants from NIH. COBRE awards provide five years of funding for multidisciplinary
teams to enhance research expertise and competitiveness within their institutions. For
more information, visit www.ncrr.nih.gov/resinfra/cobre.asp.
The General Clinical Research Center (GCRC) at the University of Oklahoma
Health Sciences Center is one of 82 GCRCs nationwide. GCRCs provide optimal
settings for inpatient and outpatient clinical studies. For more informtion, visit
www.ncrr.nih.gov/clinical/cr_gcrc.asp.
12 NCRR Reporter : Spring 2005
RESEARCH BRIEFS
Virus Implicated In Lupus
New research supports the view that
systemic lupus erythematosus, commonly
known as lupus, can result from a viral infec-
tion. In what seems to be a case of mistaken
identity, the body apparently thinks it is attack-
ing the common Epstein-Barr virus (EBV) when in fact it is tar-
geting a protein found in the body’s own cells. Lupus is an
autoimmune disease, in which misdirected antibodies, or autoan-
tibodies, attack and injure a variety of tissues in the body.
“There’s mounting evidence that EBV may be important in
triggering these abnormal autoimmune responses,” says Judith
James, principal investigator of the new research and head of the
NCRR-supported peptide synthesis core facility at the Oklahoma
Medical Research Foundation (OMRF). Funded as part of a Cen-
ters of Biomedical Research Excel-
lence (COBRE) award to the
OMRF, the core facility provided
more than a thousand protein frag-
ments, or peptides, to study
immune responses associated with
lupus. In addition, NCRR’s Gener-
al Clinical Research Center (GCRC)
at the University of Oklahoma
Health Sciences Center helped with
the study’s statistical analysis.
To investigate how the immune
system might mistake the body’s
own proteins for EBV proteins,
James and her colleagues used syn-
thetic peptides representing por-
tions of a common cellular protein
called Ro, known to be an early target for autoantibodies in
lupus, and of an EBV antigen called Epstein-Barr virus nuclear
antigen-1 (EBNA-1). Reactions between these peptides and anti-
bodies in serum previously collected from lupus patients revealed
that EBNA-1 and Ro are both targeted by the same anti-Ro anti-
bodies. These reactions also pinpointed the specific parts of these
proteins that are attacked by the antibodies. When these target-
ed sections, or epitopes, were injected into rabbits, they triggered
autoimmune reactions, and the rabbits developed lupus-like
symptoms. This supports the idea that antibodies directed against
EBV can lead to lupus by also targeting Ro.
P H O T O B Y M I C H A E L D I C K I N S O N
The findings may lead to better diagnosis and treatment of lupus.
■ Judith James has foundthat antibodies in lupuspatients may confuse acommon cellular proteinwith an Epstein-Barr viralantigen.
Sleep Key to SpeechDevelopment,Songbirds Reveal
Despite what their mothers may think,
human infants and baby birds sound remark-
ably alike to the trained ear of a behavioral neu-
roscientist. “A few years ago, we discovered
that the young bird is doing something very
similar to babbling,” says Ofer Tchernichovski of City College
of the City University of New York (CUNY). The early vocal-
izations of both birds and humans are highly repetitive and
become more complex over time. Because of these and other
similarities, Tchernichovski and his colleagues study birds in an
effort to understand speech development in humans.
Tchernichovski’s research depends on support from one of
NR2ndHalf.Final.SP05 8/10/05 2:26 PM Page 12
NCRR Reporter : Spring 2005 13P H O T O B Y S E B A S T I E N D E R E G N AU C O U RT
the NCRR-funded Research Cen-
ters in Minority Institutions
(RCMIs), located at CUNY. RCMIs
support health research at institu-
tions that award doctorates in health-
related sciences and also enroll at least 50 percent minorities that
are underrepresented in the biomedical sciences.“The RCMI Pro-
gram is a great initiative. It helped me in so many ways,”says Tch-
ernichovski, who received his salary and research funding for his
first two years at CUNY through the RCMI. The support wasn’t
just financial; program staff provided the hands-on technical help
he needed to set up his laboratory. “They worked night and day
helping me,” says Tchernichovski.
Researchers have known that sleep is key to learning and mem-
ory in both humans and animals. According to earlier studies,
brain regions devoted to birdsong show spontaneous activity dur-
ing sleep, suggesting that birds practice their songs while sleeping.
But the effects of sleep on the development of speech had gone
unexplored, says Tchernichovski. As it turns out, he and his col-
leagues have discovered that sleep has a curious effect on how
young birds, and perhaps humans, learn to speak.
Birds learn to sing by hearing adult birds sing. Studies have
suggested that baby birds readily commit the tunes to memory
and then compare their own vocalizations to the tunes they
remember. To uncover the role of sleep in this process, Tcher-
nichovski’s team recorded 50 zebra finches continuously, from
when they first started learning to sing until adulthood. The finch-
es stayed in individual cages where the scientists could control
all aspects of the environment, including light and sounds.
To analyze the birdsongs, the team used its own software pack-
age, Sound Analysis Pro, developed earlier with RCMI funding.
The software directs a computer to record
continuously several birds at a time, dif-
ferentiate the songs from each other, and
separate the sounds into syllables. Each
bird produces about 1 million syllables
during about eight weeks of develop-
mental learning, which the program ana-
lyzes for their acoustic features, such as
frequency modulation and variance in
pitch. Throughout the day, the comput-
er can play the songs of mature zebra
finches to the young birds, which copy the
songs they hear.
The complexity of the young birds’
songs changed from day to day, as the
birds became master singers,but more changes occurred overnight
than from one day to the next, the team discovered. However,
the overnight changes were not what the team expected: the
birds sang less well, meaning they made less structured sounds,
in the morning than they did the night before. But after a few
hours of morning singing, the birds’ skills exceeded their pre-
vious day’s performance.
“The effect of sleep is counterintuitive,” says Tchernichovski.
“In the short term, it looks like sleep does negative things, but
in the long term it helps.” Oddly enough, birds that declined the
most overnight became the better singers.Additional experiments
allowed the team to rule out sleepiness or lack of overnight
practice as the cause of the poor morning performances. Also,
the morning effect diminished as the birds got older, which
points to a developmental cause.
The researchers suspect that after rehearsing songs in their
sleep, birds use the morning to explore their vocal abilities and
improve their skills at imitating. The mechanism directing these
overnight and early-morning language lessons is not clear, but
structural changes at the cellular level are likely involved. (Nature
433:710-716, 2005) —TINA ADLER
NCRR RESOURCES: City College of the City University of New York is one of
18 institutions that currently host Research Centers in Minority Institutions
(RCMIs). Information about the RCMI at CUNY can be found at
www.ccny.cuny.edu/rcmi/. To learn more about the RCMI Program, visit
www.ncrr.nih.gov/resinfra/ri_rcmi.asp.
Sleep has a curious effect onhow young birds, and perhaps
humans, learn to speak.
■ Because sleep is key tospeech development, theseyoung slumbering zebrafinches may in fact be hardat work rehearsing thesongs they heard duringthe day.
NR2ndHalf.Final.SP05 8/10/05 2:27 PM Page 13
RESEARCH TO REALIT Y
Monoclonal AntibodiesFrom laboratory tool to effective therapies.
14 NCRR Reporter : Spring 2005
Since the discovery of monoclonal anti-
bodies (MAbs) was first published 30 years ago,
these targeted biological tools have evolved from
a laboratory mainstay to effective therapies for
treating a variety of human disorders. Over the
years, NCRR-supported resources have enabled the devel-
opment and clinical evaluation of several therapeutic MAbs,
including the radiolabeled drug 131I-tositumomab, trade-
named Bexxar, which homes in on normal and malignant
B cells in patients with non-Hodgkin’s lymphoma.
Results of a phase 2 clinical trial in 76 patients, published
in February 2005 in the New England Journal of Medicine,
showed that Bexxar led to prolonged remission in more than
75 percent, and shrinkage of tumors in 95 percent, of patients
with advanced and previously untreated follicular non-
Hodgkin’s lymphoma. Although researchers have yet to per-
form a direct comparison, a single week-long course of the
less-toxic MAb-based therapy appears to produce similar
efficacy and response rates in newly diagnosed patients as stan-
dard chemotherapy regimens, which typically last for sever-
al months. “I think the reduced treatment time is the most
appealing thing about this new therapy,” says Mark Kamin-
ski, who created and developed 131I-tositumomab at the Uni-
versity of Michigan with colleague Richard Wahl.
More than two decades ago, a team of scientists created an
MAb that selectively attaches to a protein found on the sur-
faces of B cells, and Kaminski and Wahl saw an opportunity
to devise a new therapy for B-cell-type non-Hodgkin’s lym-
phoma. By attaching a potent radioactive payload—in this
case, iodine-131—to the B-cell-targeted MAb, the Michigan
researchers hoped to destroy rapidly dividing cancerous B cells
in lymphoma patients. In theory, this radioimmunotherapy
would kill B cells but leave other cells relatively unharmed.
In the early 1990s, radioimmunotherapy was in its infan-
cy—consistent success in getting it to work in the clinic was
still an elusive goal. But Kaminski and Wahl’s pioneering clin-
ical studies found that the experimental drug 131I-tositumomab
showed promise for treating non-Hodgkin’s lymphoma patients
who either failed to respond to chemotherapy or relapsed after
the treatment.By 2003, the FDA had approved the radiolabeled
drug for treating such patients.
The most recent study, how-
ever, represents a first step
toward obtaining approval for
treating newly diagnosed patients, which is the ultimate goal
of drug development projects.
Throughout 15 years of clinical evaluation and develop-
ment,Kaminski and Wahl’s team relied heavily on the resources
of the NCRR-supported General Clinical Research Center
(GCRC) at the University of Michigan, where GCRC staff per-
formed patient scans and hourly blood draws.Because radioac-
tive particles tend to escape from patients recently treated with
radioimmunotherapy, the GCRC also built a special room
to house Kaminski and Wahl’s patients and protect the staff
and other patients from the scattering radiation.“There was
no way this project could have been done without access to
the GCRC,” says Kaminski.
“Wahl and Kaminski were a peas-in-the-pod team,with each
researcher bringing his unique talents to the project,”says John
Wiley, who heads the Michigan GCRC.“Wahl had expertise in
imaging and the radiological side, while Kaminski was the
oncologist who wanted to use antibodies in combination with
a high-intensity radioligand to treat the disease.”
With approximately 15,000 new cases of follicular lym-
phoma diagnosed each year in the United States, finding
a therapy that is effective and well-tolerated will have a
profound impact. “From my perspective, having watched
this experimental therapy evolve over the years, this proj-
ect has been one of the wonderful bench-to-bedside sto-
ries that we love to see,” says Wiley. “We just wish we could
see more of them.” —RABIYA S. TUMA
P H O T O B Y M A RT I N V L O E T, U N I V E R S I T Y O F M I C H I G A N P H O T O S E RV I C E S
■ Mark Kaminski (far right) speakswith Richard Lowenthal, one of thefirst patients to receive Bexxar, asnuclear medicine technician DeniseRegan administers the drug.
NR2ndHalf.Final.SP05 8/10/05 2:27 PM Page 14
NCRR Reporter : Spring 2005 15
Meeting Seeks Inputon Enhancing Clinical and Translational ScienceIn one of the first steps in a
major effort to transform clin-
ical and translational research,
NCRR sponsored a meeting—
called “Enhancing the Disci-
pline of Clinical and Transla-
tional Sciences”—to discuss
how the National Institutes of
Health (NIH) and other
research-oriented institutions
might work together to create
a new, integrated academic
discipline of clinical and trans-
lational science. The meeting
was held in Arlington,
Virginia, on May 23, 2005.
With more than 300 bio-
medical scientists and admin-
istrators in attendance, the
goal was to generate discussion
on enhancing the translation
of basic biomedical discoveries
into more effective therapies
and improved human health.
NCRR convened the gathering
on behalf of the NIH
Roadmap initiative on Re-
engineering the Clinical
Research Enterprise. Discus-
sions focused in part on the
need for clinical research
informatics; education, train-
ing, and career development;
intra- and inter-institutional
collaborations; and compre-
hensive integration and expan-
sion of resources.
In his opening remarks,
NIH Director Elias Zerhouni
noted that NIH intends to
take a more cohesive,
systems-based approach to
strengthening clinical and
translational science by creat-
ing funding programs that are
flexible enough to be tailored
to the needs and strengths of
individual institutions. He
asked participants to think
creatively about how NIH
might help to bolster clinical
and translational research at
both the institutional and the
national levels. “We realize
that no one has all the
answers, and we clearly
believe that one size does not
fit all,” Zerhouni said. “The
biggest challenge, in my view,
is to be able to develop good
science across disciplines.
Collaboration is going to be
the key to making progress.”
At the close of the meeting,
participants issued a series of
observations and recommen-
dations for NIH to consider in
developing new initiatives and
programs for clinical and
translational science. NCRR
Acting Director Barbara Alv-
ing noted that this input would
greatly inform future NIH-
wide activities in this arena.
“The development of Dr. Zer-
houni’s vision for this initiative
requires that the NIH work
closely with the community of
researchers and the academic
health centers that choose to
respond to this funding oppor-
tunity,” she said. “By under-
taking this change in how NIH
supports clinical and transla-
tional science, we can work
together to reach our ultimate
goal—improving the health of
the nation.”
For more information
about the new clinical and
translational science initiative,
part of the NIH Roadmap for
Re-engineering the Clinical
Research Enterprise, see
“From the Director,” page 2.
For more information about
the national meeting,
including a videocast of
plenary presentations, visit
www.ncrr.nih.gov/
clinicaldiscipline.asp. ■
Awards Honor Clinical Researchers Robert J. Desnick, professor
and chair of human genetics
at Mount Sinai School of
Medicine, received the 17th
Annual Award for Excellence
in Clinical Research at the
General Clinical Research
Center (GCRC) Program
Directors Meeting, held April
29-30, 2005, in Washington,
D.C. The GCRC Program
Directors Association present-
ed the award on behalf of the
Jane and Charles Pak Founda-
tion, which funds the award
to recognize outstanding clin-
ical investigators who have
conducted studies at GCRCs
within the previous decade.
Desnick received the
$5,000 award in honor of his
exceptional studies of genetic
diseases, including the rare
lysosomal storage disease
known as Fabry’s disease. He
and his colleagues showed that
lysosomal storage diseases can
be effectively treated by using
enzyme replacement, bone
marrow transplant, or other
novel techniques. Of particu-
lar note, Desnick’s basic,
translational, and clinical
research over more than three
decades ultimately led to a
Food and Drug Administra-
tion-approved treatment (Fab-
razyme) for patients with
Fabry’s disease.
Recently named a member
of the National Academy of
Sciences, Desnick is a past pro-
gram director of the Mount
Sinai GCRC (1991-1999) and a
past member of the NCRR
National Advisory Research
Resources Council (2000-
2004). He has authored more
than 365 peer-reviewed articles.
[continued on back cover ➤]
NEWS FROM NCRR People, Awards, Grants, and New Developments
ROBERT J. DESNICK
NR2ndHalf.Final.SP05 8/10/05 2:27 PM Page 15
NEWS FROM NCRR[ continued from page 15 ]
U.S. Department of Health and Human ServicesNational Institutes of Health
National Center for Research Resources
One Democracy Plaza, 9th Floor
6701 Democracy Blvd. MSC 4874
Bethesda, MD 20892-4874
Official Business
Penalty for Private Use, $300
At the Clinical Research
2005 meeting, held in tandem
with the GCRC Program
Directors Meeting, John
Eisenach of the Mayo Clinic
received the $2,000 GCRC
Outstanding Trainee Award.
Eisenach was recognized for
an abstract he presented on
isometric exercise. His study
demonstrates that a common
genetic variation in the beta-2
receptor—a receptor in the
heart, blood vessels, airway
smooth muscle, and
elsewhere—influences heart
and blood vessel response to
isometric exercise. “This find-
ing provides further evidence
that known gene variations
play an important role in how
our body regulates heart func-
tion and blood pressure,” Eise-
nach explains.
Eisenach has an NCRR
Patient-Oriented Research
Career Development Award,
or K23 grant. The K23 pro-
NEWS FROM NCRR
gram supports physicians or
dentists for three to five years
as they train in advanced and
experimental clinical research
methods. Eisenach received
his medical degree from the
University of Colorado Health
Sciences Center in Denver and
completed his residency in
anesthesiology at the Mayo
Graduate School of Medicine. ■
Multimedia ProductWins AwardA multimedia educational
tool created with NCRR sup-
port has won a coveted inter-
national award. The Pirelli
Internetional Award competi-
tion this year gave one of its
top prizes—15,000 euros, or
about $18,000—to the makers
of an interactive multimedia
tutorial called the Microar-
rays MediaBook. Each year,
the Pirelli Group, a multina-
tional corporation headquar-
tered in Milan, presents
awards for the best Web-
based multimedia products.
Produced by the Institute
for Science Learning (ISL) at
the University of North Car-
olina at Chapel Hill, the
Microarrays MediaBook uses
3-D animations and dynamic,
interactive learning tools—
aimed at a variety of learning
styles—to help undergraduate
students understand the role
of microarrays in genomics
and bioinformatics. ISL’s
MediaBook project, funded
primarily by a Small Business
Technology Transfer Research
grant through the National
Human Genome Research
Institute, receives supplemen-
tal support from NCRR and
the National Institute of Gen-
eral Medical Sciences.
The Microarrays Media-
Book is the first learning mod-
ule of a larger MediaBook that
will contain about 60 or 70
interconnected modules cov-
ering all major aspects of
genomics and bioinformatics,
says ISL Director Walter E.
“Skip” Bollenbacher. The
modules will be sold as inter-
active Web-based tutorials,
although some, including the
microarrays module, also may
be released as CD-ROMs bun-
dled to conventional
textbooks. The Microarrays
MediaBook could be available
as early as this fall, says Bol-
lenbacher, with the complete
MediaBook slated for release
in January 2007. ■
Presorted StandardU.S. Postage Paid
DHHS/NIH/RRPermit No. G-818
JOHN EISENACH
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